Antihistamines, such as H1 histamine receptor antagonists (herein referred to as “H1 antagonists” or “antihistamines”), are used to treat seasonal allergic rhinitis (SAR) and can be used to treat nasal congestion, e.g., stuffed or blocked nasal passages. Epidemiological, biological and clinical studies have shown that viral respiratory infections before the age of 3 years play a crucial role in the later development of rhinitis and asthma. Reduction of their frequency and severity may effect the viral alteration of the pulmonary and immune systems.
A new class of specific anti-influenza agents, the neuraminidase inhibitors, has demonstrated potent inhibition of both influenza A and B viruses. These inhibitors are potent and selective inhibitor of influenza A and B virus neuraminidases. Oseltamivir and zanamivir are approved for treatment of uncomplicated acute illness caused by influenza A or B virus in persons greater than or equal to twelve years of age and who have been symptomatic for no more than two days.
Oseltamivir (TAMIFLU™, OS, GS4104, EN 241104, RO 64-0796, oseltamivir phosphate, an antiviral neuraminidase inhibitor) is used for the treatment of viral infections; however, it does not treat nasal congestion. Oseltamivir is the ethyl ester prodrug of the carbocyclic transition state sialic acid analog RO 64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraminidases. Oral oseltamivir was approved for treatment of acute influenza in the United States in 1999. It has demonstrated efficacy both in treating and preventing influenza illness.
Zanamivir (RELENZA™, GG167, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a recognized neuraminisase inhibitor useful in the treatment or prevention of influenza virus infection. Zanamivir is generally thought to have poor oral bioavailability due to poor dissolution in the gastrointestinal tract. Khare et al. (Expert Opin. Pharmacother. (March 2000), 1(3), 367–375) state that the poor oral bioavailability and rapid renal clearance of zanamivir limit its use to inhalation. Cass et al. (Clin. Pharmacokinet. (1999), 36 Suppl., 1, 1–11) disclose the results of a comparison study on the pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration. They reported that approximately 90% of the zanamivir was excreted unchanged in the urine and that it was well tolerated at all doses. They also reported that the absolute oral bioavailability of zanamivir was low, averaging 2%, and after intranasal or oral inhaled administration, a median of 10 to 20% of the dose was systemically absorbed, with maximum serum concentrations generally reached within 1 to 2 hours. The median serum half-life ranged between 2.5 and 5.05 hours.
(+/−)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N′-ethyl-N′-isopropylcarbamyl) pyrrolidine-4-carboxylic acid (A-192558, 20e) and 4-(acetylamino)-3-hydroxy-5-nitrobenzoic acid are also recognized neuraminidase inhibitors useful in the treatment or prevention of influenza virus infection.
Peramivir ((1S,2S,3R,4R)-3-[(1 S)-(acetylamino)-2-ethylbutyl]-4-[(aminoimino-methyl) amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270201, BCX-1812) is also a recognized neuraminidase inhibitor useful in the treatment or prevention of influenza virus infection.
For antiviral agents to be effective, they must generally be used within 48 hours of the onset of influenza symptoms (Bantia et al. in Antimicrobial Agents and Chemotherapy, (April 2001), 45(4), 1162–1167). Antiviral agents reduce the duration of fever and illness by one to two and one-half days and also reduce the severity of some symptoms. Although, oseltamivir reduces the severity of some symptoms, it does not reduce nasal congestion or the production of excessive mucous in the respiratory tract to the same degree that an H1 histamine receptor antagonist does. Consequently, nasal congestion or the production of excessive mucous in the respiratory tract lingers in patients having been administered oseltamivir.
G. He et al. (Clin. Pharmacokinet. (1999 Dec), 37(6), pp. 471–484) report that oral administration of oseltamivir delivers the active antiviral RO 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. They report that the pharmacokinetic profile of oseltamivir is simple and predictable, and that twice-daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is reportedly about 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours with the dosage form used in that study. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. The pharmacokinetic profile of the active metabolite is reportedly linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration with the dosage form used in that study. At a dosage of 75 mg twice daily, the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75 mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are reportedly qualitatively similar to those in healthy young adults.
J. Gwaltney (U.S. Pat. No. 5,240,694, No. 5,492,689, and No. 5,422,097 discloses COVAM (combined virostatic antimediator) therapy, which includes a method and compositions for the treatment of the common cold. The method requires the nasal administration of an antiviral composition, optionally containing an antihistamine, and the concurrent oral administration of at least one anti-inflammatory agent. Gwaltney does not disclose a method or composition for the effective treatment of the common cold or other viral infections wherein both the antiviral agent and the antihistamine agent are administered orally. Moreover, Gwaltney does not disclose or suggest a dual release oral solid dosage form containing oseltamivir and an H1 antagonist.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 4,008,719 to Theeuwes et al., U.S. Pat. No. 4,058,122 to Theeuwes et al., U.S. Pat. No. 4,116,241 to Theeuwes et al., U.S. Pat. No. 4,160,452 to Theeuwes, U.S. Pat. No. 4,256,108 to Theeuwes, and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference. In particular, tablet formulations for providing antihistamines are disclosed in U.S. Pat. No. 4,650,807 to Findlay et al., and U.S. Pat. No. 4,501,893 to Findlay et al., the entire disclosures of which are hereby incorporated by reference.
Dual release conventional sustained release dosage forms are known for the concurrent or sequential administration of two or more drugs by a single unit dosage form. To date, none of the art discloses a dual release oral dosage form that provides a controlled release of an antiviral agent and a rapid release of an H1 antihistamine, or a controlled or sustained release of oseltamivir and a rapid or immediate release of an H1 antihistamine.
While conventional sustained release dosage forms, such as described above, are effective, osmotic devices such as those described by Faour et al. (U.S. Pat. No. 6,004,582), the entire disclosure of which is hereby incorporated by reference, are particularly advantageous for delivering two different dosage forms from a single osmotic device tablet. Faour et al., however, do not disclose osmotic device formulations comprising slow (controlled/sustained/extended) release neuraminidase inhibitor combined with a rapid (immediate) release H1 antagonist. They also do not disclose osmotic devices that provide the specific formulations, plasma profiles or release profiles for the various different combinations claimed herein. A need remains for improved controlled release formulations of poorly water soluble neuraminidase inhibitors.